This application aims at deciphering the molecular pathways supporting satellite cell function and at understanding how these are influenced during aging. Age-related skeletal muscle deterioration (sarcopenia) is characterized by a decline in mass, strength, endurance and repair capacity, and by fat accumulation between and within myofibers. Myofiber repair is enabled by satellite cells, myogenic stem cells situated underneath the myofiber basal lamina. Subtle muscle injuries that occur during routine muscle activity raise a continuous demand for functional myofiber repair throughout life. However, satellite cell performance declines in old age and this decline can be a contributory factor to sarcopenia. While satellite cells have classically been thought to function as tissue-specific myogenic progenitors, we have shown that they can also enter a mesenchymal alternative path, which culminates in terminal adipogenic differentiation. Such an alternative lineage commitment may contribute to impaired myogeneity and increased muscle adipostiy in old age. Gaining insight into mechanisms involved in impairing satellite cell self-renewal and myogeneity, and in promoting their mesenchymal plasticity, will contribute to the design of therapies to improve the number and function of myogenic progenitors in aging muscle. Accordingly, the aims of this proposal are: 1) Investigate the potential of satellite cells to contribute myogenic progeny and undergo self-renewal throughout life. 2) Determine the role of the myogenic transcription factors Myf5 and MyoD, and the muscle integrin alpha7, in the balance between myogenic versus mesenchymal alternative fate of satellite cells. 3) Investigate the effect of metalloproteinase and disintegrin activities on mesenchymal fate and self-renewal of satellite cells. Wildtype and genetically modified mice, of age groups ranging from juvenile to senile, will be investigated. Satellite cell performance will be examined in isolated myofibers and clones, using protein and RNA expression methodologies. Additionally, the functional role of relevant genes will be determined by transducing satellite cells with viral-based expression vectors. The proposed studies will contribute new insight into the status of satellite cells in adult and aging muscles, and will, therefore, provide important information for muscle rehabilitation strategies during disease and aging. Skeletal muscle repair is enabled by myogenic progenitors named satellite cells. Age-associated decline in the performance of these cells can be a contributory factor to the deterioration of skeletal muscle in old age (sarcopenia). The proposed studies will contribute new insight into the regulation of satellite cell function throughout the lifespan and will, therefore, provide important information for muscle rehabilitation strategies during disease and aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MOSS-L (07))
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Williams, John
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University of Washington
Anatomy/Cell Biology
Schools of Medicine
United States
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Stuelsatz, Pascal; Shearer, Andrew; Yablonka-Reuveni, Zipora (2014) Ancestral Myf5 gene activity in periocular connective tissue identifies a subset of fibro/adipogenic progenitors but does not connote a myogenic origin. Dev Biol 385:366-79
Keire, Paul; Shearer, Andrew; Shefer, Gabi et al. (2013) Isolation and culture of skeletal muscle myofibers as a means to analyze satellite cells. Methods Mol Biol 946:431-68
Shefer, Gabi; Rauner, Gat; Stuelsatz, Pascal et al. (2013) Moderate-intensity treadmill running promotes expansion of the satellite cell pool in young and old mice. FEBS J 280:4063-73
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Danoviz, Maria Elena; Yablonka-Reuveni, Zipora (2012) Skeletal muscle satellite cells: background and methods for isolation and analysis in a primary culture system. Methods Mol Biol 798:21-52
Choi, Sun Ju; Yablonka-Reuveni, Zipora; Kaiyala, Karl J et al. (2011) Increased energy expenditure and leptin sensitivity account for low fat mass in myostatin-deficient mice. Am J Physiol Endocrinol Metab 300:E1031-7
Yablonka-Reuveni, Zipora (2011) The skeletal muscle satellite cell: still young and fascinating at 50. J Histochem Cytochem 59:1041-59
Ieronimakis, Nicholas; Balasundaram, Gayathri; Rainey, Sabrina et al. (2010) Absence of CD34 on murine skeletal muscle satellite cells marks a reversible state of activation during acute injury. PLoS One 5:e10920
Xia, Chun-hong; Yablonka-Reuveni, Zipora; Gong, Xiaohua (2010) LRP5 is required for vascular development in deeper layers of the retina. PLoS One 5:e11676

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